Cocaine abuse is a persistent public health problem, but the search for medications effective for the treatment of cocaine dependence has been largely unsuccessful. Promising open trials with various therapeutic agents have led to negative findings in larger, double-blind, placebo controlled trials. This proposal describes a method to test novel compounds rapidly, using small double-blind placebo controlled "early Phase II" trials. Such small trials can screen out candidate medications that are not promising either because they ineffective or because they have side effects that would make clinically inappropriate. In keeping with the overall direction of this MDRU, we have selected four agents that modulate the dopaminergic system indirectly via their actions on excitatory or inhibitory amino acid systems. In 2 three-arm blind placebo controlled trials, we will first test GV 196771A, a selective antagonist at the glycine binding site on the NMDA subtype of glutamate receptor, and baclofen, a GABA-B agonist. We will then test acamprosate, a ligand at the polyamine binding site on the NMDA receptor and abecarnil, a partial agonist at the GABA-A receptor. Sixty treatment-seeking cocaine- dependent volunteers will complete each trial (20 on each medication and 20 on placebo), and each trial will be completed in two and one half years. The trials will be conducted at STARS, where we have demonstrated a steady record on successfully recruiting and retaining research volunteers. This proposal is particularly innovative because of how unique methodology for screening promising medications, our expertise in the field of cocaine abuse research, and the theoretical rationale for the agents we plan to test. In addition, the project is a necessary bridge between Project 1, in which medications that are more clinically advanced will be tested in late Phase II trials, and Project 3, in which less clinically advanced medications will be tested in late Phase I trials. We believe the this unique approach to screening candidate medications is a necessary step in the search for pharmacotherapy for cocaine abuse.